Indications and Usage
Lorazepam tablets areindicated for the management of anxietydisorders or for theshort-termrelief of the symptoms of anxiety or anxietyassociatedwithdepressivesymptoms.Anxiety or tensionassociatedwith the stress of everyday life usuallydoesnotrequiretreatmentwith an anxiolytic.
The effectiveness of lorazepam tablets in long-termuse,thatis,morethan 4 months,has not been assessed by systematicclinicalstudies. The physicianshouldperiodicallyreassess the usefulness of the drug for the individualpatient.
Dosage and Administration
Lorazepam tablets are administeredorally. For optimalresults,dose,frequency of administration,andduration of therapyshould be individualizedaccording to patientresponse. To facilitatethis,0.5mg, 1 mg,and 2 mgtabletsareavailable.
The usualrange is 2 to 6 mg/daygivenindivideddoses, the largestdosebeingtakenbeforebedtime, but the dailydosagemayvaryfrom 1 to 10 mg/day.
For anxiety,mostpatientsrequireaninitialdose of 2 to 3 mg/daygiventwotimes a day or threetimes a day.
For insomnia due to anxiety or transientsituationalstress, a singledailydose of 2 to 4 mgmay be given,usuallyatbedtime.
For elderly or debilitatedpatients,aninitialdosage of 1 to 2 mg/day in divideddoses is recommended, to be adjustedasneededandtolerated.
The dosageoflorazepam tablets should be increasedgraduallywhenneeded to helpavoidadverse effects.Whenhigherdosage is indicated, the eveningdoseshouldbeincreasedbefore the daytimedoses.
Discontinuation or Dosage Reduction of Lorazepam Tablets
To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam tablets or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence ).
Contraindications
Lorazepam is contraindicated in patientswith:
- hypersensitivity to benzodiazepines or to anycomponents of the formulation
- acutenarrow-angleglaucoma.
Adverse Reactions
Mostadversereactions to benzodiazepines,includingCNSeffectsandrespiratorydepression,aredose dependent,withmoresevereeffectsoccurringwithhighdoses.
In a sample of about3500patientstreated for anxiety, the mostfrequentadversereaction to lorazepam wassedation(15.9%),followedbydizziness(6.9%),weakness(4.2%),andunsteadiness(3.4%). The incidence of sedationandunsteadinessincreasedwithage.
Otheradversereactions to benzodiazepines,includinglorazepam arefatigue,drowsiness,amnesia,memoryimpairment,confusion,disorientation,depression,unmasking of depression,disinhibition,euphoria,suicidalideation/attempt,ataxia,asthenia,extrapyramidalsymptoms,convulsions/seizures,tremor,vertigo,eyefunction/visualdisturbance(includingdiplopiaandblurredvision),dysarthria/slurred speech,change in libido,impotence,decreasedorgasm;headache,coma;respiratorydepression,apnea,worsening of sleepapnea,worsening of obstructivepulmonarydisease;gastrointestinalsymptoms includingnausea,change in appetite,constipation,jaundice,increase in bilirubin,increase in liver transaminases,increase in alkalinephosphatase;hypersensitivityreactions,anaphylactoidreactions;dermatologicalsymptoms,allergicskinreactions,alopecia;syndrome of inappropriateantidiuretic hormone(SIADH),hyponatremia;thrombocytopenia,agranulocytosis,pancytopenia;hypothermia;andautonomicmanifestations.
Paradoxicalreactions,includinganxiety,excitation,agitation,hostility,aggression,rage,sleepdisturbances/insomnia,sexualarousal,andhallucinationsmayoccur.Small decreases in blood pressure andhypotensionmayoccur but areusually not clinicallysignificant,probablybeingrelated to therelief of anxietyproducedbylorazepam.
To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA Asites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.
The benzodiazepines, including lorazepam, produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics.
Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest.
Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate.
Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid.
The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation.
Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.
Drug Abuse and Dependence
Controlled Substance
Lorazepam tablets contains lorazepam, a Schedule IV controlled substance.
Abuse
Lorazepam is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.
Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS: Abuse, Misuse, and Addiction ).
The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.
The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).
Dependence
Physical Dependence
Lorazepam may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see WARNINGS: Dependence and Withdrawal Reactions ).
To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam or reduce the dosage (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of lorazepam and WARNINGS ).
Acute Withdrawal Signs and Symptoms
Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures and suicidality.
Protracted Withdrawal Syndrome
Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.
Tolerance
Tolerance to lorazepam may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of lorazepam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.
Overdosage
Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Abuse, Misuse , and Addiction ). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.
In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.
Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
Description
Lorazepam USP,anantianxietyagent,has the chemicalformula,7-chloro-5-(
o-chlorophenyl)-1,3-dihydro-3-hydroxy-2
H-1,4-benzodiazepin-2-one:
It is a nearlywhitepowderalmostinsoluble in water.Eachlorazepam tablet, USP to be takenorally,contains 0.5 mg, 1 mg, or 2 mg of lorazepam, USP. The inactiveingredientspresent are anhydrous lactose, magnesium stearate, microcrystalline cellulose, and polacrilin potassium.
Clinical Pharmacology
Studies in healthyvolunteersshowthat in singlehighdoseslorazepam has a tranquilizingaction on the centralnervoussystemwith no appreciableeffect on the respiratory or cardiovascularsystems.
Lorazepam is readilyabsorbedwithanabsolutebioavailability of 90%.Peakconcentrations in plasmaoccurapproximately 2 hoursfollowingadministration. The peakplasmalevel of lorazepam from a 2 mgdose is approximately 20 ng/mL.
The meanhalf-life of unconjugatedlorazepam inhumanplasma is about 12 hoursand for its majormetabolite,lorazepam glucuronide,about 18 hours.Atclinicallyrelevantconcentrations,lorazepam isapproximately 85% bound to plasmaproteins.Lorazepam is rapidlyconjugatedatits3-hydroxy group into lorazepam glucuronidewhich is thenexcreted in the urine. Lorazepam glucuronidehas no demonstrablecentralnervoussystem(CNS)activityinanimals.
The plasmalevels of lorazepam areproportionaltothedosegiven. There is no evidence of accumulation of lorazepam onadministrationup to 6 months.
Studiescomparing young andelderlysubjectshaveshownthatadvancingagedoes not have a significanteffect on the pharmacokinetics of lorazepam.However, in one studyinvolvingsingleintravenousdoses of 1.5 to 3 mg of lorazepam Injection,meantotalbodyclearance of lorazepam decreasedby20% in 15 elderlysubjects of 60 to 84 years of agecompared to that in 15youngersubjects of 19 to 38 years of age.
How Supplied / Storage and Handling
Lorazepam Tablets, USP are available in the following dosage strengths:
2 mg, white to off-white, round, flat-faced beveled edge tablets debossed with a bisect separating “U” and “34” on one side and “2” on other side.
Bottles of 30 tablets NDC 72789-339-30
Keep bottles tightly closed.
Keep out of reach of children.
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as described in the USP.
Dispense with Medication Guide available at:
www.aurobindousa.com/medication-guides
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling ( Medication Guide).
Risks from Concomitant Use with Opioids
Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when lorazepam is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use of Opioids and PRECAUTIONS: Drug Interactions ).
Abuse, Misuse, and Addiction
Inform patients that the use of lorazepam even at recommended doses, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug (see WARNINGS: Abuse Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ).
Withdrawal Reactions
Inform patients that the continued use of lorazepam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of lorazepam may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of lorazepam may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ).
Pregnancy
Advise pregnant females that use of lorazepam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy ). Instruct patients to inform their healthcare provider if they are pregnant.
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lorazepam during pregnancy (see PRECAUTIONS: Pregnancy ).
Nursing
Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using lorazepam to monitor infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs (see PRECAUTIONS: Nursing Mothers ).